DNA damage (naturally occurring)
DNA damage is an alteration in the chemical structure of DNA, such as a break in a strand of DNA, a base missing from the backbone of DNA, or a chemically changed base such as 8-OHdG. Damage to DNA that occurs naturally can result from metabolic or hydrolytic processes. Metabolism releases compounds that damage DNA including reactive oxygen species, reactive nitrogen species, reactive carbonyl species, lipid peroxidation products and alkylating agents, among others, while hydrolysis cleaves chemical bonds in DNA.De Bont R, van Larebeke N. (2004) Endogenous DNA damage in humans: a review of quantitative data. Mutagenesis 19(3):169-185. Review. PMID 15123782 Naturally occurring DNA damages arise about 10,000 to 100,000 times per day per mammalian cell. DNA damage is distinctly different from mutation, although both are types of error in DNA. DNA damage is an abnormal chemical structure in DNA, while a mutation is a change in the sequence of standard base pairs. DNA damage and mutation have different biological consequences. While most DNA damages can undergo DNA repair, such repair is not 100% efficient. Un-repaired DNA damages accumulate in non-replicating cells, such as cells in the brains or muscles of adult mammals and can cause aging.Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1-47. open access, but read only https://www.novapublishers.com/catalog/product_info.php?products_id=43247 ISBN 978-1604565812Hoeijmakers JH. (2009) DNA damage, aging, and cancer. N Engl J Med. 361(15):1475-1485. Review. PMID 19812404Freitas AA, de Magalhães JP. (2011) A review and appraisal of the DNA damage theory of ageing. Mutat Res. 728(1-2):12-22. Review. PMID 21600302 (Also see DNA damage theory of aging.) In replicating cells, such as cells lining the colon, errors occur upon replication of past damages in the template strand of DNA or during repair of DNA damages. These errors can give rise to mutations or epigenetic alterations.O'Hagan HM, Mohammad HP, Baylin SB. (2008) Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island. PLoS Genet. 4(8):e1000155. PMID 18704159 Both of these types of alteration can be replicated and passed on to subsequent cell generations. These alterations can change gene function or regulation of gene expression and possibly contribute to progression to cancer. DNA damages are a major problem for life One indication that DNA damages are a major problem for life is that DNA repair processes, to cope with ubiquitously occurring DNA damages, have been found in all cellular organisms in which DNA repair has been investigated. For example, in bacteria, a regulatory network aimed at repairing DNA damages (called the SOS response in Escherichia coli) has been found in many bacterial species. E. coli RecA, a key enzyme in the SOS response pathway, is the defining member of a ubiquitous class of DNA strand-exchange proteins that are essential for homologous recombination, a pathway that maintains genomic integrity by repairing broken DNA.Bell JC, Plank JL, Dombrowski CC, Kowalczykowski SC. (2012) Direct imaging of RecA nucleation and growth on single molecules of SSB-coated ssDNA. Nature 491(7423):274-278. doi: 10.1038/nature11598. PMID 23103864 Genes homologous to RecA and to other central genes in the SOS response pathway are found in almost all the bacterial genomes sequenced to date, covering a large number of phyla, suggesting both an ancient origin and a widespread occurrence of recombinational repair of DNA damage.Erill I, Campoy S, Barbé J. (2007) Aeons of distress: an evolutionary perspective on the bacterial SOS response. FEMS Microbiol Rev. 31(6):637-656. Review. PMID 17883408 Eukaryotic recombinases that are homologues of RecA are also widespread in eukaryotic organisms. For example, in fission yeast and humans, RecA homologues promote duplex-duplex DNA-strand exchange needed for repair of many types of DNA lesions.Murayama Y, Kurokawa Y, Mayanagi K, Iwasaki H. (2008) Formation and branch migration of Holliday junctions mediated by eukaryotic recombinases. Nature 451(7181):1018-1021. PMID 18256600Holthausen JT, Wyman C, Kanaar R. (2010) Regulation of DNA strand exchange in homologous recombination. DNA Repair (Amst) 9(12):1264-1272. PMID 20971042 Another indication that DNA damages are a major problem for life is that cells make large investments in DNA repair processes. As pointed out by Hoeijmakers, repairing just one double-strand break could require more than 10,000 ATP molecules, as used in signaling the presence of the damage, the generation of repair foci, and the formation (in humans) of the RAD51 nucleofilament (an intermediate in homologous recombinational repair). (RAD51 is a homologue of bacterial RecA.) Frequencies of endogenous DNA damages The list below shows some frequencies with which new naturally occurring DNA damages arise per day, due to endogenous cellular processes. * Oxidative damages ** Humans, per cell per day ***10,000Ames BN, Shigenaga MK, Hagen TM. (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U S A. 90(17):7915-7922. Review. PMID 8367443 11,500Helbock HJ, Beckman KB, Shigenaga MK, Walter PB, Woodall AA, Yeo HC, Ames BN. (1998) DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine. Proc Natl Acad Sci U S A. 95(1): 288-293. PMID 9419368 2,800Foksinski M, Rozalski R, Guz J, Ruszkowska B, Sztukowska P, Piwowarski M, Klungland A, Olinski R. (2004) Urinary excretion of DNA repair products correlates with metabolic rates as well as with maximum life spans of different mammalian species. Free Radic Biol Med 37(9) 1449-1454. PMID 15454284 specific damages 8-oxoGua, 8-oxodG plus 5-HMUra ** Rats, per cell per day ***74,000 86,000Fraga CG, Shigenaga MK, Park JW, Degan P, Ames BN. Oxidative damage to DNA during aging: 8-hydroxy-2'-deoxyguanosine in rat organ DNA and urine. Proc Natl Acad Sci U S A 1990;87(12) 4533-4537. PMID 2352934 100,000 **Mice, per cell per day ***34,000 specific damages 8-oxoGua, 8-oxodG plus 5-HMUra *Depurinations **Mammalian cells, per cell per day ***2,000 to 10,000Lindahl T, Nyberg B. (1972) Rate of depurination of native deoxyribonucleic acid. Biochemistry 11(19) 3610-3618. PMID 4626532Lindahl T. (1993) Instability and decay of the primary structure of DNA. Nature 362(6422) 709-715. PMID: 8469282 9,000Nakamura J, Walker VE, Upton PB, Chiang SY, Kow YW, Swenberg JA. Highly sensitive apurinic/apyrimidinic site assay can detect spontaneous and chemically induced depurination under physiological conditions. Cancer Res 1998;58(2) 222-225. PMID 9443396 12,000Lindahl T. (1977) DNA repair enzymes acting on spontaneous lesions in DNA. In: Nichols WW and Murphy DG (eds.) DNA Repair Processes. Symposia Specialists, Miami p225-240. ISBN 088372099X ISBN 978-0883720998 13,920Tice, R.R., and Setlow, R.B. (1985) DNA repair and replication in aging organisms and cells. In: Finch EE and Schneider EL (eds.) Handbook of the Biology of Aging. Van Nostrand Reinhold, New York. Pages 173-224. ISBN 0442225296 ISBN 978-0442225292 *Depyrimidinations **Mammalian cells, per cell per day ***600 696 *Single-strand breaks **Mammalian cells, per cell per day ***55,200 *Double-strand breaks **Human cells, per cell cycle ***10Haber JE. (1999) DNA recombination: the replication connection. Trends Biochem Sci 24(7) 271-275. PMID 10390616 50Vilenchik MM, Knudson AG. (2003) Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer. Proc Natl Acad Sci U S A 100(22) 12871-12876. PMID 14566050 *O6-methylguanines **Mammalian cells, per cell per day ***3,120 *Cytosine deamination ** Mammalian cells, per cell per day ***192 Another important endogenous DNA damage is M1dG, short for (3-(2'-deoxy-beta-D-erythro-pentofuranosyl)-pyrimido1,2-a-purin-10(3H)-one). The excretion in urine (likely reflecting rate of occurrence) of M1dG may be as much as 1,000-fold lower than that of 8-oxodG.Chan SW, Dedon PC. (2010) The biological and metabolic fates of endogenous DNA damage products. J Nucleic Acids 2010:929047. PMID 21209721 However, a more important measure may be the steady-state level in DNA, reflecting both rate of occurrence and rate of DNA repair. The steady-state level of M1dG is higher than that of 8-oxodG.Kadlubar FF, Anderson KE, Häussermann S, Lang NP, Barone GW, Thompson PA, MacLeod SL, Chou MW, Mikhailova M, Plastaras J, Marnett LJ, Nair J, Velic I, Bartsch H. (1998) Comparison of DNA adduct levels associated with oxidative stress in human pancreas. Mutat Res. 405(2):125-33. PMID 9748537 This points out that some DNA damages produced at a low rate may be difficult to repair and remain in DNA at a high steady-state level. Both M1dGVanderVeen LA, Hashim MF, Shyr Y, Marnett LJ. Induction of frameshift and base pair substitution mutations by the major DNA adduct of the endogenous carcinogen malondialdehyde. (2003) Proc Natl Acad Sci U S A 100(24):14247-14252. PMID 14603032 and 8-oxodGTan X, Grollman AP, Shibutani S. (1999) Comparison of the mutagenic properties of 8-oxo-7,8-dihydro-2'-deoxyadenosine and 8-oxo-7,8-dihydro-2'-deoxyguanosine DNA lesions in mammalian cells. Carcinogenesis 20(12):2287-2292. PMID 10590221 are mutagenic. Steady-state levels of DNA damages Steady-state levels of DNA damages represent the balance between formation and repair. More than 100 types of oxidative DNA damage have been characterized, and 8-oxodG constitutes about 5% of the steady state oxidative damages in DNA.Hamilton ML, Guo Z, Fuller CD, Van Remmen H, Ward WF, Austad SN, Troyer DA, Thompson I, Richardson A. (2001) A reliable assessment of 8-oxo-2-deoxyguanosine levels in nuclear and mitochondrial DNA using the sodium iodide method to isolate DNA. Nucleic Acids Res. 29(10):2117-26. PMID 11353081 Helbock et al.Helbock HJ, Beckman KB, Shigenaga MK, Walter PB, Woodall AA, Yeo HC, Ames BN. (1998) DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine. Proc Natl Acad Sci U S A 95(1):288-293. PMID 9419368 estimated that there were 24,000 steady state oxidative DNA adducts per cell in young rats and 66,000 adducts per cell in old rats. This reflects the accumulation of DNA damage with age. DNA damage accumulation with age is further described in DNA damage theory of aging. Swenberg et al.Swenberg JA, Lu K, Moeller BC, Gao L, Upton PB, Nakamura J, Starr TB. (2011) Endogenous versus exogenous DNA adducts: their role in carcinogenesis, epidemiology, and risk assessment. Toxicol Sci. 120 Suppl 1:S130-45. PMID 21163908 measured average amounts of selected steady state endogenous DNA damages in mammalian cells. The seven most common damages they evaluated are shown in Table 1. Evaluating steady-state damages in specific tissues of the rat, Nakamura and SwenbergNakamura J, Swenberg JA. (1999) Endogenous apurinic/apyrimidinic sites in genomic DNA of mammalian tissues. Cancer Res. 59(11):2522-2526. PMID 10363965 indicated that the number of abasic sites varied from about 50,000 per cell in liver, kidney and lung to about 200,000 per cell in the brain. Consequences of naturally occurring DNA damages Differentiated somatic cells of adult mammals generally replicate infrequently or not at all. Such cells, including, for example, brain neurons and muscle myocytes, have little or no cell turnover. Non-replicating cells do not generally generate mutations due to DNA damage-induced errors of replication. These non-replicating cells do not commonly give rise to cancer, but they do accumulate DNA damages with time that likely contribute to aging (see DNA damage theory of aging). In a non-replicating cell, a single-strand break or other type of damage in the transcribed strand of DNA can block RNA polymerase II catalysed transcription.Kathe SD, Shen GP, Wallace SS. (2004) Single-stranded breaks in DNA but not oxidative DNA base damages block transcriptional elongation by RNA polymerase II in HeLa cell nuclear extracts. J Biol Chem. 279(18):18511-18520. PMID 14978042 This would interfere with the synthesis of the protein coded for by the gene in which the blockage occurred. Brasnjevic et al.Brasnjevic I, Hof PR, Steinbusch HW, Schmitz C. (2008) Accumulation of nuclear DNA damage or neuron loss: molecular basis for a new approach to understanding selective neuronal vulnerability in neurodegenerative diseases. DNA Repair (Amst). 7(7):1087-1097. PMID 18458001 summarized the evidence showing that single-strand breaks accumulate with age in the brain (though accumulation differed in different regions of the brain) and that single-strand breaks are the most frequent steady-state DNA damages in the brain. As discussed above, these accumulated single-strand breaks would be expected to block transcription of genes. Consistent with this, as reviewed by Hetman et al.,Hetman M, Vashishta A, Rempala G. (2010) Neurotoxic mechanisms of DNA damage: focus on transcriptional inhibition. J Neurochem. 114(6):1537-1549. doi: 10.1111/j.1471-4159.2010.06859.x. Review. PMID 20557419 182 genes were identified and shown to have reduced transcription in the brains of individuals older than 72 years, compared to transcription in the brains of those less than 43 years old. When 40 particular proteins were evaluated in a muscle of rats, the majority of the proteins showed significant decreases during aging from 18 months (mature rat) to 30 months (aged rat) of age.Piec I, Listrat A, Alliot J, Chambon C, Taylor RG, Bechet D. (2005) Differential proteome analysis of aging in rat skeletal muscle. FASEB J. 19(9):1143-5. PMID 15831715 Another type of DNA damage, the double strand break, was shown to cause cell death (loss of cells) through apoptosis.Carnevale J, Palander O, Seifried LA, Dick FA. (2012) DNA damage signals through differentially modified E2F1 molecules to induce apoptosis. Mol Cell Biol. 32(5):900-912. PMID 22184068 This type of DNA damage would not accumulate with age, since once a cell was lost through apoptosis, its double strand damage would be lost with it. See also *Ageing *Aging brain *Direct DNA damage *DNA *DNA adduct *DNA damage theory of aging *DNA repair *DNA replication *Free Radical damage to DNA *Homologous recombination *Meiosis *Mutation *Natural competence *Origin and function of meiosis *Reactive oxygen species References Category:Ageing Category:Cellular processes Category:DNA Category:DNA repair Category:Gerontology Category:Molecular genetics Category:Mutation Category:Senescence